Interaction of human SUV3 RNA/DNA helicase with BLM helicase; loss of the SUV3 gene results in mouse embryonic lethality

Pereira, Mandy; Mason, Penelope A.; Szczęsny, Roman J.; Maddukuri, Leena; Dziwura, Sylwia; Jedrzejczak, R.; Paul, Erin; Wójcik, Andrzej; Dybczyńska, Lien; Tudek, Barbara; Bartnik, Ewa; Kłysik, Jan; Bohr, Vilhelm A.; Stępień, Piotr P.

doi:10.1016/j.mad.2007.09.001

Cited by 29 publications

(53 citation statements)

References 41 publications

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“…55 The Suv3 knockout mice die in utero. 56 Depletion of Suv3 leads to the accumulation of shortened mitochondrial RNA species, which is likely due to impaired mitochondrial RNA degradation. 54 A similar accumulation of shortened mitochondrial RNA like omega RNA and truncated mitochondrial RNA that cannot be degraded was observed in yeast Suv3 null cells.…”

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confidence: 99%

Genome-wide comprehensive analysis of human helicases

Umate¹,

Tuteja²,

Tuteja³

2011

Communicative & Integrative Biology

107

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confidence: 99%

Genome-wide comprehensive analysis of human helicases

Umate¹,

Tuteja²,

Tuteja³

2011

Communicative & Integrative Biology

107

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“…Recent data have further implicated SUV3 in maintaining mitochondrial . Although some reports stipulate a potential housekeeping role for SUV3, there is a dearth of significant data to authenticate that claim (31,32 …”

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confidence: 99%

Role of SUV3 Helicase in Maintaining Mitochondrial Homeostasis in Human Cells

Khidr

Dávila

et al. 2008

Journal of Biological Chemistry

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In yeast mitochondria, RNA degradation takes place through the coordinated activities of ySuv3 helicase and yDss1 exoribonuclease (mtEXO), whereas in bacteria, RNA is degraded via RNaseE, RhlB, PNPase, and enolase. Yeast lacking the Suv3 component of the mtEXO form petits and undergo a toxic accumulation of omega intron RNAs. Mammalian mitochondria resemble their prokaryotic origins by harboring a polyadenylation-dependent RNA degradation mechanism, but whether SUV3 participates in regulating RNA turnover in mammalian mitochondria is unclear. We found that lack of hSUV3 in mammalian cells subsequently yielded an accumulation of shortened polyadenylated mtRNA species and impaired mitochondrial protein synthesis. This suggests that SUV3 may serve in part as a component of an RNA degradosome, resembling its yeast ancestor. Reduction in the expression levels of oxidative phosphorylation components correlated with an increase in reactive oxygen species generation, whereas membrane potential and ATP production were decreased. These cumulative defects led to pleiotropic effects in mitochondria such as decreased mtDNA copy number and a shift in mitochondrial morphology from tubular to granular, which eventually manifests in cellular senescence or cell death. Thus, our results suggest that SUV3 is essential for maintaining proper mitochondrial function, likely through a conserved role in mitochondrial RNA regulation.Prokaryotes and eukaryotes both utilize RNA processing and degradation, albeit via different pathways, as one mechanism for controlling gene expression (1-4). The RNA degradosome of Escherichia coli, yeast, and mammalian cells have all conserved the ability to turnover RNA; however, the assembly of their multicomponent machineries differ (5, 6). In E. coli, RNA degradation is conducted by the cooperation of four principal enzymes (7). The first enzyme is an endoribonuclease, RNase E, which initiates the turnover of many RNAs by cleaving singlestranded RNA internally and is essential for cell growth (2,8,9). The second enzyme is a 50-kDa DEAD-box helicase, RhlB, which unwinds and translocates RNA substrates (10). RhlB facilitates the degradation of structured mRNA decay intermediates by the third 85-kDa enzyme, polynucleotide polymerase (PNPase).3 This process, requiring ATP hydrolysis, is believed to involve the local unwinding of structures that block PNPase, thereby ensuring rapid degradation by PNPase (11-13). The fourth enzyme, a 48-kDa glycolytic enzyme enolase, associates with RNase E in response to stress caused by the overabundance of phosphosugars (14, 15). However, enolase is a unique and mysterious contributor to the degradosome, as it is not an RNA-binding protein nor does it appear to be directly involved in RNA turnover.In Saccharomyces cerevisiae, mitochondrial RNA degradation also requires the activity of multifunctional components (mtEXO) (16), which consist mainly of two enzymes: ySuv3 and yDss1 (17)(18)(19)(20). Yeast Suv3 is a nuclear gene-encoded protein that localizes to mitochondria in ...

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“…Human SUPV3L1 is important for maintaining mitochondrial homeostasis (20) and has been shown to degrade double-stranded RNA (21). However, SUPV3L1 also appears to function in the cytoplasm, interacting with the WRN and BLM DNA helicases to suppress mitotic homologous recombination (13). Mice homozygous for a genetrap insertion in the SUPV3L1 gene die in utero before midgestation (13).…”

Section: Discussionmentioning

confidence: 99%

“…However, SUPV3L1 also appears to function in the cytoplasm, interacting with the WRN and BLM DNA helicases to suppress mitotic homologous recombination (13). Mice homozygous for a genetrap insertion in the SUPV3L1 gene die in utero before midgestation (13). Conditional inactivation of murine SUPV3L1 by Mx1-Cre leads to a defective skin barrier and premature aging (22).…”

Section: Discussionmentioning

confidence: 99%

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Conditional control of gene function by an invertible gene trap in zebrafish

Ni¹,

Zhu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Conditional mutations are essential for determining the stage-and tissue-specific functions of genes. Here we achieve conditional mutagenesis in zebrafish using FT1, a gene-trap cassette that can be stably inverted by both Cre and Flp recombinases. We demonstrate that intronic insertions in the gene-trapping orientation severely disrupt the expression of the host gene, whereas intronic insertions in the neutral orientation do not significantly affect host gene expression. Cre-and Flp-mediated recombination switches the orientation of the gene-trap cassette, permitting conditional rescue in one orientation and conditional knockout in the other. To illustrate the utility of this system we analyzed the functional consequence of intronic FT1 insertion in supv3l1, a gene encoding a mitochondrial RNA helicase. Global supv311 mutants have impaired mitochondrial function, embryonic lethality, and agenesis of the liver. Conditional rescue of supv311 expression in hepatocytes specifically corrected the liver defects. To test whether the liver function of supv311 is required for viability we used Flp-mediated recombination in the germline to generate a neutral allele at the locus. Subsequently, tissue-specific expression of Cre conditionally inactivated the targeted locus. Hepatocyte-specific inactivation of supv311 caused liver degeneration, growth retardation, and juvenile lethality, a phenotype that was less severe than the global disruption of supv311. Thus, supv311 is required in multiple tissues for organismal viability. Our mutagenesis approach is very efficient and could be used to generate conditional alleles throughout the zebrafish genome. Furthermore, because FT1 is based on the promiscuous Tol2 transposon, it should be applicable to many organisms.H igh throughput functional genomic and informatic methods have been developed to interrogate the genome and extract functional predictions about many genes at a time. However, careful phenotypic analysis of genetic mutants remains the sine qua non of reductionist biological science. In most experimental organisms, random mutagenesis is the preferred or only mutagenic technique available. DNA alkylating agents, transposable elements, or retroviruses are traditionally used in these organisms. A major limitation of these traditional genetic methods is that they reveal only the earliest and/or most prominent function of a gene as later functions are masked by the earlier phenotype, which is often lethality. To assess later functions, for example in metabolism, aging, or behavior, conditional alleles are required.The development of conditional alleles has proven a boon to studying gene function in temporally or spatially restricted contexts. Traditional conditional alleles disrupt gene function by changing the environment, for example by increasing the temperature. Engineered conditional alleles disrupt gene function by activating a recombination-mediated molecular switch that ablates gene function in one state, but has no functional consequences in the other state (1, 2...

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Interaction of human SUV3 RNA/DNA helicase with BLM helicase; loss of the SUV3 gene results in mouse embryonic lethality

Cited by 29 publications

References 41 publications

Genome-wide comprehensive analysis of human helicases

Genome-wide comprehensive analysis of human helicases

Role of SUV3 Helicase in Maintaining Mitochondrial Homeostasis in Human Cells

Conditional control of gene function by an invertible gene trap in zebrafish

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